The present invention relates generally to compounds and methods for use in modulating xcex2-catenin mediated gene expression and cellular differentiation. The invention is more specifically related to modulating agents capable of affecting the interaction between xcex2-catenin and transcription factors, and to therapeutic methods employing such agents.
xcex2-catenin is a cytoplasmic protein that is critical for classical cadherin-mediated intercellular adhesion. Inside the cell, a xcex2-catenin/xcex1-catenin complex interacts with the second cytoplasmic domain (CP2) of the classical cadherins. In the absence of this xcex2-catenin/xcex1-catenin complex, the classical cadherins cannot promote cell adhesion (see Wheelock et al., Current Topics in Membranes 43:169-185, 1996).
In addition to its role in cell adhesion, xcex2-catenin is also a key component of certain cellular signaling pathways, leading to activation of gene expression and a variety of developmental and disease processes, such as differentiation, cancer and Alzheimer""s disease. In particular, xcex2-catenin functions in Wnt-mediated signaling, associating with LEF-1/TCF DNA binding proteins to form a transcription factor (see Willert and Nusse, Genetics and Development 8:95-102, 1998). xcex2-catenin-mediated signaling is involved in a variety of developmental processes, including cellular differentiation. For example, skin cells expressing a stabilized form of xcex2-catenin display increased hair growth (Gat et al., Cell 95:605-614, 1998; Ono et al., Cell 95:575-578, 1998). Thus, therapies based on modulating xcex2-catenin mediated gene expression have potential for altering cell differentiation and, in certain instances, hair growth. Such therapies could further be used in the treatment of cancer and Alzheimer""s disease. However, there are presently no available therapies for inhibiting xcex2-catenin-mediated signaling.
Accordingly, there is a need in the art for improved methods for modulating xcex2-catenin-mediated signal transduction and cellular differentiation. The present invention fulfills this need and further provides other related advantages.
The present invention provides methods for inhibiting xcex2-catenin mediated gene transcription and cellular differentiation. Within certain aspects, the present invention provides modulating agents comprising one or more of: (a) the amino acid sequence LXXLL (SEQ ID NO:1); or (b) a peptide analogue or peptidomimetic of the amino acid sequence LXXLL (SEQ ID NO:1). Within certain embodiments, the modulating agent comprises the sequence LXXLL (SEQ ID NO:1) within a linear peptide or a cyclic peptide ring. Such modulating agents may, within certain embodiments, comprise a linear or cyclic peptide ranging from 3 to 16 amino acid residues in length. A modulating agent may further comprise an internalization moiety, such as an internalization sequence covalently linked to the modulating agent, a liposome that encapsulates the modulating agent or an antibody or ligand that binds to a cell surface receptor. Within further embodiments, any of the above modulating agents may be linked to a targeting agent and/or a drug.
Within other aspects, the present invention provides pharmaceutical compositions comprising a modulating agent as described above, in combination with a pharmaceutically acceptable carrier.
Within further related aspects, the present invention provides methods for modulating the activation of xcex2-catenin mediated gene transcription in a cell, comprising contacting a cell with a modulating agent as described above.
Within further related aspects, the present invention provides methods for modulating differentiation of a cell, comprising contacting a cell with a modulating agent as described above.
In other aspects, methods are provided for modulating hair growth on a mammal, comprising administering to a mammal a modulating agent as described above. Such administration may be topical.
The present invention further provides, within other aspects, methods for treating cancer and/or inhibiting metastasis in a patient, comprising administering to a patient a modulating agent as described above.
Within further aspects, the present invention provides methods for inhibiting the development of Alzheimer""s disease in a patient, comprising administering to a patient a modulating agent as described above.
The present invention further provides methods for modulating the activity of a retinoic acid receptor and/or androgen receptor in a cell, comprising contacting a cell with a modulating agent as described above.